Elderly patients with chronic obstructive pulmonary disease (COPD) and those with more severe airway limitation are perceived to experience reduced efficacy from inhaled bronchodilators, especially ...those administered in a dry powder inhaler. This study compared the efficacy and safety of a long-acting muscarinic antagonist/long-acting β
-agonist dry powder combination in elderly patients with COPD and patients with moderate-to-very severe airflow limitation.
This post hoc pooled analysis of seven randomized studies of ≥12 weeks' duration investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 μg versus tiotropium (TIO) 18 μg or fluticasone propionate/salmeterol (FP/SAL) 250/50 μg. Change from baseline in trough forced expiratory volume in 1 s (FEV
), a common efficacy measure in all trials, proportion of FEV
responders (≥100 mL increase from baseline) and safety outcomes were analyzed at Day 28, 56, and 84 in patients classified by age (<65, ≥65, and ≥75 years of age) and severity of baseline airflow limitation (Global initiative for chronic Obstructive Lung Disease GOLD stage 2 moderate and stage 3/4 severe/very severe). A 24-week analysis was also conducted for the UMEC/VI versus TIO comparison.
The pooled intent-to-treat population comprised 3821 patients (≥65 years: 44-45%; ≥75 years: 9-10%; GOLD stage 3/4: 50-55%); 2246, 874, and 701 patients received UMEC/VI, TIO, or FP/SAL, respectively. Significant improvements in trough FEV
at Day 84 were observed with UMEC/VI versus TIO or FP/SAL irrespective of age (all p ≤ 0.029) or GOLD stage (all p < 0.001). The proportion of FEV
responders at Day 84 was significantly greater with UMEC/VI versus TIO or FP/SAL across all age groups (all p ≤ 0.016) and GOLD stages (all p < 0.001). Safety profiles were similar between treatment groups.
UMEC/VI consistently demonstrated improved lung function versus TIO and FP/SAL across age and airflow limitation severity subgroups, with no safety concerns, indicating that UMEC/VI provides no loss in efficacy or additional safety concerns for both elderly patients with COPD and patients with severe/very severe airway limitation.
Introduction
We report the results of the first direct comparison of the once-daily fixed-dose long-acting muscarinic antagonist/long-acting β
2
-agonist (LAMA/LABA) combinations ...umeclidinium/vilanterol (UMEC/VI) and tiotropium/olodaterol (TIO/OLO) in patients with COPD.
Methods
This was a randomized, two-period crossover open-label study in symptomatic patients with COPD age 40 years or older, postbronchodilator forced expiratory volume in 1 s (FEV
1
) of 70% or less and 50% or more of predicted normal values, and modified Medical Research Council Dyspnoea Scale score of 2 or greater not receiving inhaled corticosteroid therapy. Patients were randomized to receive UMEC/VI (62.5/25 µg once daily) via a multidose dry powder inhaler (ELLIPTA) followed by TIO/OLO (5/5 µg once daily) via a soft mist inhaler (Respimat), each for 8 weeks with an interim 3-week washout or vice versa. The primary end point was the change from baseline in trough FEV
1
at week 8 with a noninferiority margin of − 50 mL in the per-protocol (PP) population. The incidence of adverse events was also assessed.
Results
In total, 236 patients (mean age 64.4 years, 60% male) were included in the intent-to-treat population and 227 were included in the PP population. UMEC/VI treatment was noninferior in the PP population and superior in the intent-to-treat population to TIO/OLO treatment with regard to trough FEV
1
at week 8 FEV
1
change from baseline 180 mL vs 128 mL; difference 52 mL (95% confidence interval 28–77 mL);
p
< 0.001. Patients receiving UMEC/VI had twofold increased odds of experiencing a clinically meaningful increase (100 mL or more) from baseline in trough FEV
1
at week 8 compared with patients receiving TIO/OLO (odds ratio 2.05; 95% confidence interval 1.34–3.14). Adverse events occurred in 25% of patients in the UMEC/VI group and in 31% of patients in the TIO/OLO group.
Conclusion
In this first direct comparison of two once-daily fixed-dose LAMA/LABA combinations, superiority was observed for the primary end point of trough FEV
1
at week 8 with UMEC/VI compared with TIO/OLO in patients with symptomatic COPD. Both treatments had similar safety profiles. These findings confirm the results of previous indirect LAMA/LABA comparisons, and show that an efficacy gradient exists within the LAMA/LABA class.
Trial Registration
ClinicalTrials.gov identifier NCT02799784.
Funding
GlaxoSmithKline.
...the conclusion is based on one post hoc exacerbation analysis performed during the last of three 8-week intervals, whereas seven other analyses of exacerbations showed no significant difference ...between treatments. Guidelines state that the minimum period for assessing exacerbations should be 6 months.3 These guidelines also suggest that changes in concomitant therapy, e.g. exacerbation treatment, can make outcomes less reliable over time. ...it is essential for all data from the point of randomisation to be incorporated in any exacerbation rate.
The cost-effectiveness of long-acting muscarinic antagonist (LAMA) umeclidinium bromide (UMEC) 62.5 μg as add-on therapy to other maintenance COPD treatments is unknown.
This analysis assessed the ...cost-effectiveness of the following in COPD: UMEC + fluticasone furoate/vilanterol 100/25 μg (FF/VI); UMEC + fluticasone propionate/salmeterol 250/50 μg (FP/SAL); and UMEC + several alternative choices of inhaled corticosteroid/long-acting β2-agonist (ICS/LABA). The model was informed with direct and indirect data from previously published studies, with a UK perspective and a lifetime horizon. Sensitivity analyses were also performed.
For the lifetime horizon, compared with FF/VI, FP/SAL and ICS/LABAs, addition of UMEC was associated with incremental costs per quality-adjusted life-years (QALY) of £4050, £7210 and £5780, respectively, and incremental costs per life year gain of £3380, £6020 and £4940. All UMEC-containing regimens resulted in numerically lower exacerbation rates versus comparator regimens over a lifetime horizon.
Addition of UMEC to various ICS/LABA treatments was associated with higher cost than ICS/LABA alone, but was cost-effective in most scenarios.
•UMEC + ICS/LABA was associated with greater QALY gains than ICS/LABA alone.•UMEC + ICS/LABA was slightly more costly than ICS/LABA alone.•UMEC + ICS/LABA resulted in numerically lower exacerbation rates than ICS/LABA.•UMEC + ICS/LABA was cost-effective in most scenarios versus ICS/LABA alone.
Minimizing the risk of disease progression and exacerbations is the key goal of COPD management, as these are well-established indicators of poor COPD prognosis. We developed a novel composite end ...point assessing three important aspects (lung function, health status, and exacerbations) of worsening in COPD. The objective was to determine whether dual bronchodilation with umeclidinium/vilanterol (UMEC/VI) reduces clinically important deteriorations (CIDs) in COPD versus placebo or bronchodilator monotherapy.
This study is a post hoc analysis of two 24-week trials comparing UMEC/VI 62.5/25 µg with UMEC 62.5 µg, VI 25 µg, or placebo (Study A; NCT01313650), or UMEC/VI 62.5/25 µg with tiotropium (TIO) 18 µg (Study B; NCT01777334) in patients with symptomatic COPD, without a history of frequent exacerbations. Deterioration was assessed as the time to a first CID, a composite measure defined as a decrease of ≥100 mL in trough forced expiratory volume in 1 second or ≥4-unit increase in St George's Respiratory Questionnaire total score or an on-treatment moderate-to-severe COPD exacerbation.
In Study A, fewer patients experienced a first CID with UMEC/VI (44%) versus UMEC (50%), VI (56%), and placebo (75%). The risk of a first CID was reduced with UMEC/VI (hazard ratio HR: 0.37 95% confidence interval, CI: 0.30, 0.45), UMEC (HR: 0.46 95% CI: 0.38, 0.56), and VI (HR: 0.55 95% CI: 0.45, 0.66; all P<0.001) versus placebo, and with UMEC/VI versus UMEC (HR: 0.80 95% CI: 0.65, 0.97; P<0.05) and versus VI (HR: 0.67 95% CI: 0.55, 0.81; P<0.001). In Study B, fewer patients experienced a first CID with UMEC/VI (41%) versus TIO (59%). UMEC/VI reduced the risk of a first composite CID by 43% versus TIO (HR: 0.57 95% CI: 0.47, 0.69; P<0.001).
This exploratory analysis, using a new assessment of clinical deterioration in COPD, revealed that a majority of symptomatic patients with low exacerbation risk experienced a deterioration during the 24-week study periods. UMEC/VI reduces the risk of a first CID versus placebo or bronchodilator monotherapy.
Introduction
Dual bronchodilator therapy is reserved as a second-line treatment in patients with chronic obstructive pulmonary disease (COPD) and provides benefits in lung function and health status ...versus monotherapy. The aim of this study was to determine whether early initiation of a dual bronchodilator versus monotherapy reduced the risk of deterioration in COPD.
Methods
This post hoc pooled analysis investigated the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 mcg/day compared with tiotropium (TIO) 18 mcg/day in a maintenance-naïve (MN) subgroup of patients relative to the intent-to-treat (ITT) population from three 6-month active comparator studies (
n
= 1747). Other treatment arms (UMEC/VI 125/25, VI 25 and UMEC 125) comprised 850 patients in total but were not included in this analysis. The primary endpoint was trough forced expiratory volume in 1 s (FEV
1
). St George’s Respiratory Questionnaire (SGRQ) score, rescue medication use, and a novel composite endpoint of short-term clinically important deterioration (CID; ≥100 ml decrease in trough FEV
1
, ≥4-unit increase in SGRQ score, or a COPD exacerbation) were also assessed.
Results
UMEC/VI improved trough FEV
1
versus TIO at day 169 least squares mean (95% confidence interval): MN: 146 ml (102–189) and ITT: 95 ml (71–118); both
P
< 0.001. Both UMEC/VI and TIO improved SGRQ and rescue use in the two populations, with greater improvements in rescue use with UMEC/VI versus TIO. UMEC/VI reduced the risk of short-term clinically important deterioration versus TIO hazard ratio; 95% confidence interval: MN: 0.66 (0.51–0.85); ITT: 0.62 (0.54–0.71), both
P
≤ 0.001. Adverse events were similar across both populations and treatments.
Conclusions
Early use of dual-bronchodilator therapy has superior efficacy on lung function and may reduce the risk of short-term deterioration compared to monotherapy in symptomatic patients with COPD.
Clinical trial registration
: GSK analysis 202066 (NCT01316900/DB2113360, NCT01316913/DB2113374, NCT01777334/ZEP117115).
Funding
: This study was funded by GSK.
Objective
The aim of this pooled analysis was to assess the efficacy and safety of umeclidinium/vilanterol (UMEC/VI) 62.5/25 µg dual bronchodilation versus placebo in elderly symptomatic patients ...with chronic obstructive pulmonary disease (COPD).
Methods
We conducted a post hoc pooled analysis of data from 10 randomized controlled trials (RCTs). Change from baseline (CFB) in trough forced expiratory volume in 1 s (FEV
1
), proportion of FEV
1
responders (≥ 100-mL increase from baseline), and safety were analyzed in patients aged < 65, ≥ 65, and ≥ 75 years on Days 28, 56, and 84 (12-week analysis of parallel-group design studies), Days 28, 56, 84, 112, 140, 168, and 169 (24-week analysis of parallel-group design studies), and Days 2, 42, and 84 (12-week analysis of crossover design studies).
Results
The UMEC/VI intent-to-treat (ITT) populations comprised 2246, 1296, and 472 patients in the 12-week parallel-group, 24-week parallel-group, and 12-week crossover analysis, respectively (≥ 65 years: 36–44%; ≥ 75 years: 7–11%). The placebo ITT populations comprised 528, 280, and 505 patients, respectively (≥ 65 years: 37–41%; ≥ 75 years: 5–11%). Significant improvements in trough FEV
1
and significantly greater proportions of FEV
1
responders were seen with UMEC/VI compared with placebo in all analyses regardless of patient age or timepoint considered (
p
≤ 0.023), except Day 84 trough FEV
1
CFB in the 12-week crossover analysis in patients aged ≥ 75 years (
p
= 0.064). UMEC/VI safety profile was similar to placebo in all age groups.
Conclusions
In this pooled analysis of RCT data, once-daily UMEC/VI was well tolerated and provided clinically significant lung function benefits compared with placebo in younger and older patients with COPD.
Funding
GlaxoSmithKline (study 208125).
Clinically important deterioration (CID) in chronic obstructive pulmonary disease (COPD) is a novel composite endpoint that assesses disease stability. The association between short-term CID and ...future economic and quality of life (QoL) outcomes has not been previously assessed. This analysis considers 3-year data from the TOwards a Revolution in COPD Health (TORCH) study, to examine this question.
This post hoc analysis of TORCH (NCT00268216) compared costs and utilities at 3 years among patients without CID (CID-) and with CID (CID+) at 24 weeks. A positive CID status was defined as either: a deterioration in forced expiratory volume in 1 second (FEV
) of ≥100 mL from baseline; or a ≥4-unit increase from baseline in St George's Respiratory Questionnaire (SGRQ) total score; or the incidence of a moderate/severe exacerbation. Patients from all treatment arms were included. Utility change was based on the EQ-5D utility index. Costs were based on healthcare resource utilization from 24 weeks to end of follow-up combined with unit costs for the UK (2016 GBP), and reported as per patient per year (PPPY). Adjusted estimates were generated controlling for baseline characteristics, treatment assignment, and number of CID criteria met.
Overall, 3,769 patients completed the study and were included in the analysis (stable CID- patients, n=1,832; unstable CID+ patients, n=1,937). At the end of follow-up, CID- patients had higher mean (95% confidence interval CI) utility scores than CID+ patients (0.752 0.738, 0.765 vs 0.697 0.685, 0.71; difference +0.054;
<0.001), and lower costs PPPY (£538 vs £916; difference: £378 95% CI: £244, £521;
<0.001). The cost differential was primarily driven by the difference in general hospital ward days (
=0.003).
This study demonstrated that achieving early stability in COPD by preventing short-term CID is associated with better preservation of future QoL alongside reduced healthcare service costs.
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